Overexpression of the M2 isoform of pyruvate kinase is an adverse prognostic factor for signet ring cell gastric cancer

AIM:To investigate M2 isoform of pyruvate kinase(PKM2) expression in gastric cancers and evaluate its potential as a prognostic biomarker and an anticancer target.METHODS:All tissue samples were derived from gastric cancer patients underwent curative gastrectomy as a primary treatment.Clinical and pathological information were obtained from the medical records.Gene expression microarray data from 60 cancer and 19 noncancer gastric tissues were analyzed to evaluate the expression level of PKM2 mRNA.Tissue microarrays were constructed from 368 gastric cancer patients.Immunohistochemistry was used to measure PKM2 expression and PKM2 positivity of cancer was determined by proportion of PKM2-positive tumor cells and staining intensity.Association between PKM2 expression and the clinicopathological factors was evaluated and the correlation between PKM2 and cancer prognosis was evaluated.RESULTS:PKM2 mRNA levels were increased more than 2-fold in primary gastric cancers compared to adjacent normal tissues from the same patients(log transformed expression level:7.6 ± 0.65 vs 6.3 ± 0.51,P < 0.001).Moreover,differentiated type cancers had significantly higher PKM2 mRNA compared to undifferentiated type cancers(log transformed expression level:7.8 ± 0.70 vs 6.7 ± 0.71,P < 0.001).PKM2 protein was mainly localized in the cytoplasm of primary cancer cells and detected in 144 of 368(39.1%) human gastric cancer cases.PKM2 expression was not related with stage(P = 0.811),but strongly correlated with gastric cancer differentiation(P < 0.001).Differentiated type cancers expressed more PKM2 protein than did the undifferentiated ones.Well differentiated adenocarcinoma showed 63.6% PKM2-positive cells;in contrast,signet-ring cell cancers showed only 17.7% PKM2-positive cells.Importantly,PKM2 expression was correlated with shorter overall survival(P < 0.05) independent of stage only in signet-ring cell cancers.CONCLUSION:PKM2 expression might be an adverse prognostic factor for signet-ring cell carcinomas.Its function and potential as a prognostic marker should be further verified in gastric cancer.

Overexpression of miR-196b and HOXA10 characterize a poor-prognosis gastric cancer subtype

AIM:To identify molecular biologic differences between two gastric adenocarcinoma subgroups presenting different prognoses through the analysis of microRNA and protein expression.METHODS:Array technologies were used to generate1146 microRNAs and 124 proteins expression profiles of samples from 60 patients with gastric cancer.For the integrative analysis,we used established mRNA expression data published in our previous study.Whole mRNA expression levels were acquired from microarray data for 60 identical gastric cancer patients.Two gastric adenocarcinoma subgroups with distinct mRNA expression profiles presented distinctly different prognoses.MicroRNA and protein expression patterns were compared between gastric cancer tissue and normal gastric tissue and between two different prognostic groups.Aberrantly expressed microRNA,associated mRNA,and protein in patients with poor-prognosis gastric cancer were validated by quantitative reverse transcription polymerase chain reaction and immunochemistry in independent patients.RESULTS:We obtained the expression data of 1146microRNAs and 124 cancer-related proteins.Four microRNAs were aberrantly expressed in the two prognostic groups and in cancer vs non-cancer tissues(P<0.05).In the poor-prognosis group,miR-196b,miR-135b,and miR-93 were up-regulated and miR-29c*was down-regulated.miR-196b expression positively correlated with Homeobox A10(HOXA10)expression(r=0.726,P<0.001),which was significantly increased in poor-prognosis patients(P<0.001).Comparing gastric cancer with non-cancer tissues,46/124 proteins showed differential expression(P<0.05);COX2(P<0.001)and cyclin B1(P=0.017)were clearly overexpressed in the poor-prognosis group.CONCLUSION:Co-activation of miR-196b and HOXA10characterized a poor-prognosis subgroup of patients with gastric cancer.Elucidation of the biologic function of miR-196b and HOXA10 is warranted.